1. Field of the Invention
The invention relates generally to dopamine agonists and more particularly to bis(benzylpyrrolidine) derivatives which are orally active dopamine agonists.
2. Background of the Invention
Dopamine, 4-(2-aminoethyl)-1,2-benzenediol, is a marketed sympathomimetic with significant dopaminergic actions in the periphery. Drugs having the pharmacological effect of dopamine are referred to as dopaminergic agonists; some sympathomimetics appear to act on dopamine receptors in the central nervous system. In the periphery, dopamine receptors are prominent in the splanchnic and renal vascular beds, where they mediate vasodilatation. Dilatation in these beds is important in the treatment of shock and congestive heart failure, since these beds are often critically constricted in these conditions. Dopamine is used in the management of these disorders. It may also be used to induce diuresis, probably consequent to renal vasodilatation, at least in part.
Dopamine is a natural catecholamine formed by the decarboxylation of 3,4-dihydroxyphenylalanine (DOPA). It is a precursor to norepinephrine in noradrenergic nerves and is also a neurotransmitter in certain areas of the central nervous system, especially in the nigrostriatal tract, and in a few peripheral sympathetic nerves.
In the central nervous system and the mesenteric, coronary and renal vascular beds, it acts upon dopamine receptors that are distinct from .alpha.- and .beta.-adrenoreceptors. At these dopamine receptors, haloperidol is an antagonist. In the above-named vascular beds it causes vasodilatation. The renal vasodilatation may be one stimulus for diuresis. Dopamine also has moderate .beta..sub.1 - and weak .alpha.-agonist activities, part of which is attributable to norepinephrine released by dopamine. During a low rate of intravenous infusion, only vasodilatation in the mesenteric, coronary and renal vascular beds usually predominates, and hypotension sometimes occurs. At an intermediate rate of infusion, the heart rate and force of contraction are increased, as is cardiac output, and blood pressure may increase accordingly. At high rates of infusion, .alpha.-adrenergic vasoconstriction in the mesenteric, coronary and renal vascular beds may overcome the dopaminergic vasodilatation in some recipients.
Dopamine is used in the treatment of shock, for which it has several advantages. Firstly, vasodilatation can often be effected in the two organs most likely to suffer ischemic damage in shock (kidney and small bowel); blood may be moved from the skeletal muscle to more vital organs, cardiac stimulation improves a usually deteriorated cardiac function, and diuresis also helps to preserve renal function. Although dopamine is now the vasopressor agent of choice in shock, a substantial fraction of cases nevertheless fail to respond. Dopamine is also used to treat acute heart failure; the decreased vascular resistance decreases the cardiac afterload, the cardiostimulatory actions improve cardiac output, and the diuresis lessens edema.
U.S. Pat. No. 4,613,606, issued Sep. 23, 1986, discloses a number of tetrahydroisoquinoline derivatives which are indicated as being calcium channel blockers and as such useful for the treatment of cardiovascular disorders including angina, hypertension and congestive heart failure.
European Patent Application No. 0,297,973, published Dec. 14, 1988, discloses a number of dopamine .beta.-hydroxylase (DBH) inhibitors. Dopamine is hydroxylated to norepinephrine by DBH in the presence of oxygen and ascorbic acid; and DBH inhibitors are believed to be effective in treating hypertension.